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The film focuses on the Orinoco River in Venezuela, where a strain of genetically modifiedpiranha have escaped into an isolated tributary of the river. Through human interference of the local environment, the megapiranha manage to escape from their isolated spot and swim downstream, killing all that crosses their path. The megapiranha gradually make their way towards Florida[4] at the height of the tourist season.

After the outbreak, a team including Special Agent Fitch and Sarah Monroe, work to contain the megapiranhas within Venezuela. They begin to get into trouble with the authorities when they attempt to cross over the Venezuelan border. Not having proper clearance and documentation, Special Agent Fitch resorts to using the diplomacy of his fist and drives off. He is pursued by Colonel Antonio Diaz in a high-speed chase through the jungle. Throughout the chase, Fitch alternates driving a Toyota Camry and Hyundai Elantra while Diaz is seen at different points in a GMC Jimmy, Chevrolet Suburban, Suzuki XL7, and Ford Explorer. Fitch escapes by stealing a helicopter and heads to the International Super Bunker (ISB). During the journey, the helicopter runs out of fuel and Sarah Monroe rigs the emergency oxygen tank to the fuel line to make it to the ISB safely.

The megapiranhas continue to move north, consuming two battleships and a nuclear submarine. They eventually reach south Florida, where they kill at least five Puerto Ricans on a beach and manage to blow up two hotels. Meanwhile, the only force that can stop them is located at the ISB. After the megapiranhas prove impervious to both torpedoes and depth charges—and even a nuclear torpedo fails to stop them—Special Agent Fitch and Professor Sarah Monroe conclude that the only way to stop the megapiranhas is to face them in their own terrain: underwater. An army of SCUBA divers armed with guns would make the huge fish bleed, causing them to enter a feeding frenzy and kill each other. If this were to fail, then a massive nuclear strike would be used to destroy the megapiranha, as well as most of Florida.

In the middle of the operation, Colonel Diaz arrives in a helicopter, presumably using multiple fuel tanks to do this journey. The Colonel aims to get revenge on Agent Fitch and throws a rope into the water to trick him into climbing up into the enemy helicopter. Fitch, upon his arrival, shoots the pilot in the mouth with a flare gun, which causes the pilot's head to explode. Fitch then uses a homing beacon (which is actually a canister of CO2) to attract a megapiranha, jumping out of the helicopter shortly before it is consumed by the fishy behemoth.

Fitch is pursued by the megapiranha that ate the helicopter, eventually hiding in a reef where the megapiranha is unable to follow. When the piranha opens its mouth, Fitch shoots his gun at the helicopter still in the beast's jaws. The helicopter explodes, killing the fish. The other megapiranha converge on the bloodshed and Fitch is able to escape as the piranha enters a feeding frenzy and begin tearing each other to pieces, seemingly resulting in them wiping themselves out. Sarah and Fitch make out and all is well.

The mockbuster was produced to capitalise on the 2010 film Piranha 3-D.[5] On March 29, 2010 the SyFy Channel released an exclusive sneak peek of a scene from the film[6] in anticipation of its April 10 premiere of the film.[7] On the April 7, 2010 The Asylum released the official trailer online.[8]

Dread Central wrote about the film: "Now, the question becomes whether Mega Piranha means we should expect a super-sized piranha a la Asylum's Mega Shark Versus Giant Octopus or if they are basing their film around the prehistoric Megapiranha, a toothier, three-foot version of the carnivorous fish that became extinct millions of years ago. Given the big screen 3D remake is about these Megapiranha, I would say odds are high the latter will prove the case.[9]

The film reached a 2.2 million audience for its April 10 premiere, making it the channel's most-watched movie of the year. Of those, 807,000 were adults 18-49.[10]